The present invention pertains to the field of medical research, particularly to the development of mammalian models of human rheumatoid arthritis.
Rheumatoid arthritis (RA) is a common autoimmune disease characterized by joint swelling, deformation and, ultimately, destruction, culminating in severe physical disability. De Graaf et al., in The Epidemiology of Chronic Rheumatism, Dellgren and Ball, eds. (Blackwell, Oxford, 1963), pp. 446-56; Meenam et al., Arthritis Rheum., 24:544-50 (1981); Gabriel et al., J. Rheumatol., 26:1269-74 (1999); James, Clin. Exp. Rheumatol., 17:392-93 (1999). RA is a progressive condition with well-recognized symptoms including symmetrical peripheral joint swelling and synovial inflammation while sparing the axial skeleton; the presence of rheumatoid factor (RF) autoantibodies; increased concentrations of interleukin-6 (IL-6) in serum and synovial fluid; and pregnancy-induced disease remission followed by severe postpartum flares, that is, while women with RA commonly undergo remission during pregnancy, the disease returns and may be even more severe and show a new onset or more accelerated course after delivery. See, Turgen, in Immunology and Serology in Laboratory Medicine, 2nd edition, Shanahan, ed. (Mosby Year Book, St. Louis, 1996), pp. 387-98; Hirano et al., Eur. J. Immunol., 18:1797-1801 (1988); Wilder et al., Ann. N.Y. Acad. Sci., 876:14-31 (1999); Iijima et al., J. Rheumatol., 26:755-56 (1999); Ostensen, Ann. N.Y. Acad. Sci., 876:131-43 (1999).
In medical research directed to understanding, diagnosing and treating RA, several animal models of the disease have been described, but no spontaneous animal model that closely mimics all the features of the human disease has been discovered. Thus, it would greatly advance discovery research in the field of RA research if a mammalian model faithfully exhibiting the same characteristic physical symptoms of RA could be obtained.
It has now been surprisingly discovered that a particular breed of mouse commonly used in diabetes research, i.e., the nonobese diabetic or xe2x80x9cNODxe2x80x9d mouse, can be used to produce offspring that exhibit a physical symptomology closely matching the symptomology of RA in humans suffering from the disease.
Accordingly, the present invention provides NOD mice useful as models of human rheumatoid arthritis, e.g., that exhibit joint and limb swelling, symmetrical enlargement of peripheral joints with sparing of axial skeleton (e.g., hips, spine); common tendon deformities, such as spontaneous rupture of extensor tendons and Boutonniere deformity; characteristic histological features, such as synovitis, leukocyte invasion, pannus formation, cartilage destruction and bone degeneration; and characteristic serological changes, such as autoantibodies specific for the Fc region of immunoglobulin G (IgG) and increases in proinflammatory cytokines, especially IL-6, in synovial fluid and serum. The occurrence of such symptoms in the mice, furthermore, mimcs the human disease in the pattern of progression of the disease and in disease penetration across a population. Moreover, the development of the disease in the mice shows the same disparate penetrance according to gender and the same pregnancy-correlated remission and postpartum exacerbation in females as observed in human RA sufferers.
The present invention also provides a method for preparing mouse models of human rheumatoid arthritis.